Long QT syndrome: beyond the causal mutation

Abstract

Congenital long QT syndrome (LQTS) is caused by single autosomal-dominant mutations in a gene encoding for a cardiac ion channel or an accessory ion channel subunit. These single mutations can cause life-threatening arrhythmias and sudden death in heterozygous mutation carriers. This recognition has been the basis for world-wide staggering numbers of subjects and families counselled for LQTS and treated based on finding (putative) disease-causing mutations. However, prophylactic treatment of patients is greatly hampered by the growing awareness that simple carriership of a mutation often fails to predict clinical outcome: many carriers never develop clinically relevant disease while others are severely affected at a young age. It is still largely elusive what determines this large variability in disease severity, where even within one pedigree, an identical mutation can cause life-threatening arrhythmias in some carriers while in other carriers no disease becomes clinically manifested. This suggests that additional factors modify the clinical manifestations of a particular disease-causing mutation. In this article, potential demographic, environmental and genetic factors are reviewed, which, in conjunction with a mutation, may modify the phenotype in LQTS, and thereby determine, at least partially, the large variability in disease severity.

Figure 1. Incomplete penetrance and variable expressivity

The structure of a representative multigenerational pedigree with type 1 long QT syndrome (LQT1) from the Academic Medical Center (AMC) in Amsterdam. LQT1 is caused by the IVS7+5G>A (c.842+5G>A) mutation in intron 7 of KCNQ1. The mutation displays 75% disease penetrance. Note the differences in disease severity (variable disease expressivity) between the genotype-positive (mutation-carrying) family members.

Figure 2. Modifiers of phenotype in long QT syndrome

Schematic representation of genetic and non-genetic factors that are known to modify the phenotype in the long QT syndrome, thereby contributing to incomplete penetrance and variable expressivity. Straight line reflects a direct effect (e.g. direct channel block). Dashed line reflects an indirect effect (e.g. altering gene transcription, messenger RNA translation, or channel phosphorylation). , stimulatory effect; , inhibitory effect; 5′UTR, 5′ untranslated region; 3′UTR, 3′ untranslated region; M2-R, M2 muscarinic acetylcholine receptor; β-AR, β-adrenergic receptor; Na_v1.5, I_Na channel protein; K_v11.1, I_Kr channel protein; K_v7.1, I_Ks channel protein; TNF, tumour necrosis factor; IL-1, interleukin-1.

Figure 3. The cardiac electrical activity and the long QT syndrome

A, prolongation of the QT interval on the surface electrocardiogram. B, prolongation of the action potential duration. C, schematic representation of major inward and outward currents that contribute to action potential formation in ventricular myocytes in health (straight lines), and ion current dysfunctions linked to different types of long QT syndrome (dashed lines).

Figure 4. Distribution of QTc duration in health and in long QT syndrome

Continuous line represents QTc distribution in health. Dashed line represents QTc distribution in long QT syndrome. The circles display the genetic architecture of the QTc duration consisting of very rare variants with <1% minor allele frequency (MAF) but large effect on the QTc duration, common rare variants with 1–5% MAF with an intermediate effect on QTc duration, and common variants with >5% MAF but small effect on the QTc duration. Rare variants are mutations that are traditionally linked to the long QT syndrome; however, they may be found in persons with normal QTc duration. Common variants are expected to minimally influence (prolong or shorten) the QTc duration. Common rare include variants associated with strong modifying effects on the QTc duration in the general population and variants associated with LQTS only in the co-presence of a non-genetic trigger (a ‘second hit’).

Figure 5. Allele-specific effects of variants in the 3 ′untranslated region (3′UTR) of KCNQ1 on the QTc duration and symptomatology in long QT syndrome type 1 (LQT1)

A, allele-specific effects of SNPs rs2519184, rs8234 and rs10798 in the 3′UTR of KCNQ1 on the QTc and symptomatology in patients with LQT1. B, luciferase assays in primary neonatal rat cardiomyocytes transfected with two independent reporter plasmids containing the major or the minor haplotype of SNPs in 3′UTR of KCNQ1. C, the possible mechanism where SNPs in the 3′UTR of KCNQ1 modify phenotype in LQT1. SNPs in the 3′UTR may alter the expression of the normal and the mutant KCNQ1 alleles in an allele-specific manner, and, as a result, the balance between the normal and the mutant K_v7.1 proteins within the tetrameric I_Ks channels. Numbers in bars denote group sizes. Data are presented as mean; error bars represent SEM. N, normal KCNQ1 allele; M, mutant KCNQ1 allele. Reproduced from Amin et al. (2012) © 2012 with permission from Oxford University Press. * indicates comparisons between QTc durations. # indicates comparison between symptomatology.